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Gene Review

FZD4  -  frizzled class receptor 4

Homo sapiens

Synonyms: CD344, EVR1, FEVR, FZD4S, Frizzled-4, ...
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Disease relevance of FZD4


Psychiatry related information on FZD4

  • 3. We propose that deletions of the FZD4 gene located within the centromeric segment cause retinal dysgenesis, while deletions within the telomeric segment account for dysmorphic craniofacial features, growth and mental retardation, and mild digital anomalies [6].

High impact information on FZD4

  • Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair [7].
  • Injection of wildtype and mutated FZD4 into Xenopus laevis embryos revealed that wildtype, but not mutant, frizzled-4 activated calcium/calmodulin-dependent protein kinase II (CAMKII) and protein kinase C (PKC), components of the Wnt/Ca(2+) signaling pathway [8].
  • Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization [9].
  • We show that this mutant form of Fz4 oligomerizes with wild-type Fz4, retains it in the endoplasmic reticulum and inhibits its signalling [9].
  • We also detected Wnt-2b, Wnt-4, Wnt-5a, Wnt-5b, Frizzled 4, and Frizzled 6 in differentiated epithelial and mesenchymal cells of the small intestine and colon [10].

Biological context of FZD4

  • Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q [11].
  • The FZD4 gene has been mapped to human chromosome 11q14-q21 [12].
  • CONCLUSIONS: High-resolution genotyping and haplotype analysis excluded FZD4 as the defective gene in a family previously linked to the EVR1 locus [13].
  • Molecular genetic analysis revealed that both the proband and her father had a heterozygous missense mutation of A to G at 1026 bp of the FZD4 gene (Met342Val) [14].
  • This paper describes the clinical phenotype of adFEVR in two Japanese families with two different mutations in the FZD4 gene [15].

Anatomical context of FZD4

  • Among cancer cell lines, the FZD4 mRNA level was higher in HeLa S3 [12].
  • The FZD4 mRNA of 7.7 kb in size were detected almost ubiquitously in normal human tissues and larger amounts in fetal kidney, adult heart, skeletal muscle, and ovary [12].
  • Two lines of evidence suggest that oligomerization occurs in the endoplasmic reticulum: first, a mutant allele of Fz4, encoding a truncated protein that is retained in the endoplasmic reticulum, is linked to the autosomal-dominant retinal degenerative disease, familial exudative vitreoretinopathy (FEVR) [9].
  • Norrin and Frizzled4 (Fz4) function as a ligand-receptor pair to control vascular development in the retina and inner ear [16].
  • A potential receptor for Wnt-4 in corpora lutea is Fz-4 that was also elevated in this tissue [17].

Associations of FZD4 with chemical compounds

  • FZD4 spans a total of 7392 nucleotides and encodes a 537-amino-acid protein with the N-terminal cysteine-rich domain, seven transmembrane domains, and the C-terminal S/T-X-V motif [12].
  • By using time-resolved fluorescence microscopy and GPCR conformation-sensitive FRET we found that stimulation of endothelial cells with fluid shear stress, hypotonic stress, or membrane fluidizing agent leads to a significant increase in activity of bradykinin B(2) GPCR in endothelial cells [18].
  • Several studies have argued that G-protein-coupled receptors (GPCR) have the capacity to promote activation of receptor tyrosine kinases [19].
  • M33 is functionally similar to the human cytomegalovirus-encoded US28 GPCR in its ability to induce inositol phosphate accumulation, activate NF-kappaB, and promote smooth muscle cell migration [2].
  • In Western immunoassays and in immunoprecipitations, MAb EVR1 identified a HeLa cell glycoprotein of approximately 75 kDa that is attached to the cell membrane by a glycosyl-phosphatidylinositol (GPI) anchor [3].

Regulatory relationships of FZD4


Other interactions of FZD4

  • FZD4 and FZD10 are up-regulated in NT2 cells after ATRA treatment [21].
  • METHODS: Genomic DNA samples from family members were polymerase chain reaction (PCR) amplified with fluorescently tagged microsatellite markers spanning the EVR1/EVR4 locus (11q13-14) and the EVR3 locus (11p12-13) [22].
  • BACKGROUND/AIMS: Familial exudative vitreoretinopathy (FEVR) is associated with mutations in the Norrie disease gene in X linked pedigrees and with linkage to the EVR1 locus at 11q13 in autosomal dominant cases [23].
  • METHODS: Direct sequencing following polymerase chain reaction of exons of FZD4 was performed for 24 probands with FEVR (18 familial and six sporadic), and some of their families [1].
  • In this study, we show that a multi-PDZ containing protein, MAGI-3, specifically binds to frizzled-4 and -7 [24].

Analytical, diagnostic and therapeutic context of FZD4


  1. Frizzled 4 gene (FZD4) mutations in patients with familial exudative vitreoretinopathy with variable expressivity. Kondo, H., Hayashi, H., Oshima, K., Tahira, T., Hayashi, K. The British journal of ophthalmology. (2003) [Pubmed]
  2. G Protein-coupled Receptor (GPCR) Kinase 2 Regulates Agonist-independent Gq/11 Signaling from the Mouse Cytomegalovirus GPCR M33. Sherrill, J.D., Miller, W.E. J. Biol. Chem. (2006) [Pubmed]
  3. The HeLa cell receptor for enterovirus 70 is decay-accelerating factor (CD55). Karnauchow, T.M., Tolson, D.L., Harrison, B.A., Altman, E., Lublin, D.M., Dimock, K. J. Virol. (1996) [Pubmed]
  4. A viral conspiracy: hijacking the chemokine system through virally encoded pirated chemokine receptors. Vischer, H.F., Vink, C., Smit, M.J. Curr. Top. Microbiol. Immunol. (2006) [Pubmed]
  5. Genetic variants of frizzled-4 gene in familial exudative vitreoretinopathy and advanced retinopathy of prematurity. MacDonald, M.L., Goldberg, Y.P., Macfarlane, J., Samuels, M.E., Trese, M.T., Shastry, B.S. Clin. Genet. (2005) [Pubmed]
  6. Karyotype-phenotype insights from 11q14.1-q23.2 interstitial deletions: FZD4 haploinsufficiency and exudative vitreoretinopathy in a patient with a complex chromosome rearrangement. Li, P., Zhang, H.Z., Huff, S., Nimmakayalu, M., Qumsiyeh, M., Yu, J., Szekely, A., Xu, T., Pober, B.R. Am. J. Med. Genet. A (2006) [Pubmed]
  7. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Xu, Q., Wang, Y., Dabdoub, A., Smallwood, P.M., Williams, J., Woods, C., Kelley, M.W., Jiang, L., Tasman, W., Zhang, K., Nathans, J. Cell (2004) [Pubmed]
  8. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Robitaille, J., MacDonald, M.L., Kaykas, A., Sheldahl, L.C., Zeisler, J., Dubé, M.P., Zhang, L.H., Singaraja, R.R., Guernsey, D.L., Zheng, B., Siebert, L.F., Hoskin-Mott, A., Trese, M.T., Pimstone, S.N., Shastry, B.S., Moon, R.T., Hayden, M.R., Goldberg, Y.P., Samuels, M.E. Nat. Genet. (2002) [Pubmed]
  9. Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization. Kaykas, A., Yang-Snyder, J., Héroux, M., Shah, K.V., Bouvier, M., Moon, R.T. Nat. Cell Biol. (2004) [Pubmed]
  10. Expression pattern of Wnt signaling components in the adult intestine. Gregorieff, A., Pinto, D., Begthel, H., Destrée, O., Kielman, M., Clevers, H. Gastroenterology (2005) [Pubmed]
  11. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Toomes, C., Bottomley, H.M., Jackson, R.M., Towns, K.V., Scott, S., Mackey, D.A., Craig, J.E., Jiang, L., Yang, Z., Trembath, R., Woodruff, G., Gregory-Evans, C.Y., Gregory-Evans, K., Parker, M.J., Black, G.C., Downey, L.M., Zhang, K., Inglehearn, C.F. Am. J. Hum. Genet. (2004) [Pubmed]
  12. Molecular cloning and characterization of human Frizzled-4 on chromosome 11q14-q21. Kirikoshi, H., Sagara, N., Koike, J., Tanaka, K., Sekihara, H., Hirai, M., Katoh, M. Biochem. Biophys. Res. Commun. (1999) [Pubmed]
  13. Identification of a fourth locus (EVR4) for familial exudative vitreoretinopathy (FEVR). Toomes, C., Downey, L.M., Bottomley, H.M., Scott, S., Woodruff, G., Trembath, R.C., Inglehearn, C.F. Mol. Vis. (2004) [Pubmed]
  14. Novel mutation in FZD4 gene in a Japanese pedigree with familial exudative vitreoretinopathy. Yoshida, S., Arita, R., Yoshida, A., Tada, H., Emori, A., Noda, Y., Nakao, S., Fujisawa, K., Ishibashi, T. Am. J. Ophthalmol. (2004) [Pubmed]
  15. Autosomal dominant familial exudative vitreoretinopathy in two Japanese families with FZD4 mutations (H69Y and C181R). Omoto, S., Hayashi, T., Kitahara, K., Takeuchi, T., Ueoka, Y. Ophthalmic Genet. (2004) [Pubmed]
  16. Mutational analysis of norrin-frizzled4 recognition. Smallwood, P.M., Williams, J., Xu, Q., Leahy, D.J., Nathans, J. J. Biol. Chem. (2007) [Pubmed]
  17. Regulated expression of Wnts and Frizzleds at specific stages of follicular development in the rodent ovary. Hsieh, M., Johnson, M.A., Greenberg, N.M., Richards, J.S. Endocrinology (2002) [Pubmed]
  18. G protein-coupled receptors sense fluid shear stress in endothelial cells. Chachisvilis, M., Zhang, Y.L., Frangos, J.A. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  19. Conjugated bile acids promote ERK1/2 and AKT activation via a pertussis toxin-sensitive mechanism in murine and human hepatocytes. Dent, P., Fang, Y., Gupta, S., Studer, E., Mitchell, C., Spiegel, S., Hylemon, P.B. Hepatology (2005) [Pubmed]
  20. Dishevelled 2 recruits beta-arrestin 2 to mediate Wnt5A-stimulated endocytosis of Frizzled 4. Chen, W., ten Berge, D., Brown, J., Ahn, S., Hu, L.A., Miller, W.E., Caron, M.G., Barak, L.S., Nusse, R., Lefkowitz, R.J. Science (2003) [Pubmed]
  21. Regulation of WNT signaling molecules by retinoic acid during neuronal differentiation in NT2 cells: threshold model of WNT action (review). Katoh, M. Int. J. Mol. Med. (2002) [Pubmed]
  22. Further evidence of genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of EVR1, EVR3, and EVR4 in a large autosomal dominant pedigree. Toomes, C., Downey, L.M., Bottomley, H.M., Mintz-Hittner, H.A., Inglehearn, C.F. The British journal of ophthalmology. (2005) [Pubmed]
  23. Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree. Bamashmus, M.A., Downey, L.M., Inglehearn, C.F., Gupta, S.R., Mansfield, D.C. The British journal of ophthalmology. (2000) [Pubmed]
  24. MAGI-3 is involved in the regulation of the JNK signaling pathway as a scaffold protein for frizzled and Ltap. Yao, R., Natsume, Y., Noda, T. Oncogene (2004) [Pubmed]
  25. Automatic gene collection system for genome-scale overview of G-protein coupled receptors in eukaryotes. Ono, Y., Fujibuchi, W., Suwa, M. Gene (2005) [Pubmed]
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